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EP1390023B1 - Sels pharmaceutiques des composés 1-phenyl-3-dimethylamino-propaniques - Google Patents

Sels pharmaceutiques des composés 1-phenyl-3-dimethylamino-propaniques Download PDF

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Publication number
EP1390023B1
EP1390023B1 EP02716816A EP02716816A EP1390023B1 EP 1390023 B1 EP1390023 B1 EP 1390023B1 EP 02716816 A EP02716816 A EP 02716816A EP 02716816 A EP02716816 A EP 02716816A EP 1390023 B1 EP1390023 B1 EP 1390023B1
Authority
EP
European Patent Office
Prior art keywords
dimethylamino
medicament
salt
pharmaceutical
phenol
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired - Lifetime
Application number
EP02716816A
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German (de)
English (en)
Other versions
EP1390023A2 (fr
Inventor
Johannes Bartholomäus
Heinrich Kugelmann
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Gruenenthal GmbH
Original Assignee
Gruenenthal GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Gruenenthal GmbH filed Critical Gruenenthal GmbH
Priority to SI200230712T priority Critical patent/SI1390023T1/sl
Publication of EP1390023A2 publication Critical patent/EP1390023A2/fr
Application granted granted Critical
Publication of EP1390023B1 publication Critical patent/EP1390023B1/fr
Anticipated expiration legal-status Critical
Expired - Lifetime legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • A61K9/0058—Chewing gums
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/48—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups
    • C07C215/54—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/56—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by hydroxy groups
    • C07C215/58—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by hydroxy groups with hydroxy groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
    • C07C215/62—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by hydroxy groups with hydroxy groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain the chain having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/64—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/64—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms
    • C07C217/66—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms with singly-bound oxygen atoms and six-membered aromatic rings bound to the same carbon atom of the carbon chain
    • C07C217/68—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains further substituted by singly-bound oxygen atoms with singly-bound oxygen atoms and six-membered aromatic rings bound to the same carbon atom of the carbon chain with singly-bound oxygen atoms, six-membered aromatic rings and amino groups bound to the same carbon atom of the carbon chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/54—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C217/74—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with rings other than six-membered aromatic rings being part of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D275/00—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings
    • C07D275/04—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D275/06—Heterocyclic compounds containing 1,2-thiazole or hydrogenated 1,2-thiazole rings condensed with carbocyclic rings or ring systems with hetero atoms directly attached to the ring sulfur atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D291/00—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms
    • C07D291/02—Heterocyclic compounds containing rings having nitrogen, oxygen and sulfur atoms as the only ring hetero atoms not condensed with other rings
    • C07D291/06—Six-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D489/00—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula:
    • C07D489/02—Heterocyclic compounds containing 4aH-8, 9 c- Iminoethano-phenanthro [4, 5-b, c, d] furan ring systems, e.g. derivatives of [4, 5-epoxy]-morphinan of the formula: with oxygen atoms attached in positions 3 and 6, e.g. morphine, morphinone
    • C07D489/04—Salts; Organic complexes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/14—The ring being saturated

Definitions

  • the present invention relates to pharmaceutical salts of an active ingredient and at least one sugar substitute, medicaments containing these salts and the use of these salts for the production of medicaments.
  • the formulation of pharmaceutical agents with very good water solubility to drugs often presents problems in pharmaceutical practice.
  • the production of dosage forms with controlled release is often difficult because of the very good water solubility of active compound salts.
  • a retardation of these drugs can be achieved for example by coating the drug forms with retarding film coatings.
  • retardant film coatings from aqueous coating systems for highly water-soluble active ingredients often represent only an insufficient diffusion barrier.
  • the preparation of these retarded active ingredient preparations therefore requires relatively expensive coating methods with multilayer films. If such retardant coatings are applied from organic solvents, the associated environmental and solvent residue problem additionally increases the cost of preparing corresponding preparations.
  • the object of the present invention was therefore to provide pharmaceutical compounds of active ingredients which have no bitter taste.
  • the corresponding active compounds should be easier to formulate and retard more effectively.
  • the solubility of the pharmaceutical salts according to the invention in water is ⁇ 250 mg / ml of water, preferably ⁇ 200 mg / ml, more preferably ⁇ 150 mg / ml, most preferably ⁇ 100 mg / ml.
  • the water solubility of the pharmaceutical salts of the invention over the water solubility of the best water-soluble salt of the corresponding drug according to Pharmazeutist Stoffache, 12th Edition ABDATA Pharma-Data Service, 65735 Eschborn / Taunus, preferably to the corresponding hydrochloride by at least 50%, preferably at least 65%, more preferably at least 75%, most preferably at least 85% is reduced.
  • sugar substitutes As sugar substitutes according to the invention all sugar substitutes come into question, which can form a salt with formation of an at least simply negatively charged form with the respective pharmaceutical active ingredient. Also included in the invention are pharmaceutical salts in which the active pharmaceutical ingredient has two or more different sugar substitutes as salt partners.
  • the pharmaceutical salts according to the invention preferably contain saccharin, cyclamate or acesulfame as salt-forming sugar substitutes, more preferably saccharin.
  • Suitable active ingredients according to the invention are all pharmaceutical active ingredients of the abovementioned group in question, which can form a salt in anionic form while forming an at least simply positively charged form with the respective sugar substitute (s).
  • the preparation of the pharmaceutical salts according to the invention can be carried out by customary methods known to the person skilled in the art.
  • For the preparation of the pharmaceutical salts according to the invention preferably at least one salt of the respective active substance and at least one salt of the respective one of them are separately from each other.
  • Sugar substitute dissolved in a minimum amount of a solvent or solvent mixture, optionally with heating.
  • both solutions are combined, optionally mixed and optionally cooled.
  • the pharmaceutical salt according to the invention from the active substance and the sugar substitute precipitates at least partially from the optionally cooled solution, this is separated off by customary methods, preferably by suction filtration.
  • the separated pharmaceutical salt is then, if necessary, purified by customary methods known to those skilled in the art, for example by recrystallization, washing or by stirring in a suitable solvent.
  • the remaining solution is preferably completely concentrated on a rotary evaporator and the pharmaceutical salt according to the invention is extracted from the residue by customary methods known to the person skilled in the art and purified as described above.
  • the solvent or solvent mixture suitable for the preparation and the suitable reaction conditions can be determined by a person skilled in the art with the aid of simple preliminary tests. If both the active ingredient salt and the salt of the sugar substitute have sufficient solubility in water, water is preferably used as the solvent.
  • the respective active ingredient is preferably its hydrochloride, hydrobromide, phosphate, hydrogen phosphate, hydrogen sulfate, sulfate, nitrate or methyl sulfate used.
  • the salt of the respective sugar substitute preferably its sodium, potassium, calcium or ammonium salt is used.
  • Another object of the present invention are pharmaceutical compositions containing at least one inventive pharmaceutical salt and optionally physiologically acceptable excipients.
  • the corresponding drugs can be used for the treatment of the indications known for the respective active ingredients.
  • medicaments according to the invention are used for controlling pain, which comprise at least one pharmaceutical salt according to the invention.
  • pharmaceutical compositions according to the invention contain the corresponding saccharinates as pharmaceutical salts of these active substances.
  • medicaments according to the invention are preferably used which have at least one pharmaceutical salt according to the invention.
  • the pharmaceutical compositions according to the invention contain the corresponding saccharinates as pharmaceutical salts of these active substances.
  • the medicaments of the invention may be in solid, semi-solid or liquid form.
  • the medicaments according to the invention are preferably suitable for oral administration.
  • the medicament of the invention is in the form of gel, chewing gum, juice, spray, tablet, chewing tablet, dragee.
  • the medicament according to the invention may also be formulated in multiparticulate form, preferably in the form of milk-tablet tablets, microcapsules, granules, active-ingredient crystals or pellets, more preferably in the form of microtablets, granules or pellets, optionally packed in capsules or pressed into tablets.
  • the medicament according to the invention is in the form of granules or pellets, these may preferably have a size in the range from 0.1 to 3 mm, more preferably in the range from 0.5 to 2 mm.
  • the medicament according to the invention is in the form of microtablets, they may preferably have a diameter in the range of 0.5 to 5 mm, more preferably in the range of 1 to 3 mm and most preferably in the range of 1 to 2 mm.
  • the medicament according to the invention is in the form of active ingredient crystals, microparticles, micropellets or microcapsules, these may preferably have a diameter in the range from 10 ⁇ m to 1 mm, particularly preferably in the range from 15 ⁇ m to 0.5 mm and very particularly preferably in the range from 30 microns to 200 microns.
  • the medicaments according to the invention may also contain, as further constituents, the customary physiologically compatible auxiliaries known to the person skilled in the art.
  • the medicaments according to the invention may contain as physiologically acceptable excipients preferably microcrystalline cellulose, cellulose ethers, lactose, starch, starch derivatives, sugar alcohols, calcium hydrogenphosphate and the usual binders known to the skilled person, flow regulators, lubricants and / or disintegrants ,
  • the medicaments according to the invention are in the form of gels or chewing gums, they may contain as physiologically acceptable excipients preferably methylparaben, propylparaben, xylitol and / or xanthan gum.
  • the medicaments according to the invention are in the form of pellets, granules or micropellets, they may contain, as physiologically acceptable excipients, preferably microcrystalline cellulose, cellulose ethers, lactose, starch and starch derivatives, sugar alcohols, calcium hydrogenphosphate, fatty alcohols, esters of glycerol or fatty acid esters.
  • physiologically acceptable excipients preferably microcrystalline cellulose, cellulose ethers, lactose, starch and starch derivatives, sugar alcohols, calcium hydrogenphosphate, fatty alcohols, esters of glycerol or fatty acid esters.
  • the medicaments according to the invention are in the form of microcapsules or microparticles, they can contain the customary physiologically compatible auxiliaries known to the person skilled in the art, depending on the type of process used for their preparation.
  • the preparation of the medicaments according to the invention can be carried out by customary methods known to the person skilled in the art.
  • the medicaments according to the invention are present in the form of tablets, preferably the pharmaceutical salt according to the invention and optionally the physiologically compatible excipients are mixed homogeneously with one another, then granulated by means of wet, dry or melt granulation and pressed into tablets or by direct tabletting of the pharmaceutical Salt prepared with further excipients.
  • the tablets can preferably be produced by pressing optionally coated pellets, active ingredient crystals, microparticles or microcapsules.
  • compositions of the invention in the form of pellets may preferably be prepared by mixing the pharmaceutical salt and physiologically acceptable excipients, extrusion and spheronization, by spinel pelletization or by direct pelletization in a high speed mixer or in the rotor fluidized bed. Particularly preferred is the preparation of the pellets by extrusion of wet masses and subsequent spheronization.
  • microcapsules The preparation of microcapsules is carried out by conventional microencapsulation techniques, e.g. by spray drying, spray hardening or coacervation.
  • the medicaments according to the invention in semisolid form are preferably suitable for administering the pharmaceutical salt according to the invention via the oral mucosa
  • the medicaments according to the invention in solid or liquid form such as oily or aqueous juices, tablets or multiparticulate forms are preferably suitable for application of the pharmaceutical salt according to the invention via the gastric tract.
  • the drug intake is provided only on the intestinal tract, they must have at least one enteric coating.
  • enteric coating is achieved that they pass through the gastric tract undissolved and the pharmaceutical salt is released only in the intestinal tract.
  • the enteric coating dissolves at a pH of between 5 and 7.5.
  • the medicament according to the invention may also have the pharmaceutical salt according to the invention partially or completely in a retarded form.
  • the sustained release of the active ingredient delivery is preferably based on the application of a retarding coating, on the embedding in a retarding matrix, on the attachment to an ion exchange resin or on a combination of these aforementioned retarding methods.
  • the retarding coating is based on a water-insoluble, optionally modified natural or synthetic polymer or on a natural, semi-synthetic or synthetic wax or fat or fatty alcohol or a mixture of at least two of these aforementioned components.
  • Poly (meth) acrylates more preferably poly (C 1-4 ) alkyl (meth) acrylates, poly (C 1-4 ) dialkylamino (C 1-4 ) alkyl (poly (C 1-4 ) alkyl) are preferably used as water-insoluble polymers for producing a retarding coating.
  • meth) acrylates and / or their copolymers most preferably ethyl acrylate / methyl methacrylate copolymers with a molar ratio of the monomers of 2: 1, ethyl acrylate / methyl methacrylate / trimethylammonium ethyl methacrylate chloride copolymers with a molar ratio of monomers of 1: 2: 0.1, Ethyl acrylate / methyl methacrylate / trimethylammonium ethyl methacrylate chloride copolymers having a molar ratio of Monomers of 1: 2: 0.2 or a mixture of at least two of these polymers mentioned above used as a coating material.
  • water-insoluble polymers for the production of the retarding coating for the medicaments of the invention are polyvinyl acetates, optionally in combination with other adjuvants. These are available as aqueous dispersion containing 27 wt .-% polyvinyl acetate, 2.5 wt .-% povidone and 0.3 wt .-% sodium lauryl sulfate (Kollicoat SR 30 D ® ) on the market.
  • the retarding coatings of the medicaments according to the invention are based on water-insoluble cellulose derivatives, preferably alkylcelluloses, such as, for example, ethylcellulose, or on cellulose esters, such as, for example, cellulose acetate, as a coating material.
  • the coatings of ethyl cellulose or cellulose acetate are preferably applied from aqueous Pseudolatexdispersion.
  • Aqueous ethyl cellulose pseudolatex dispersions than 30 wt% -, lge dispersions (Aquacoat ®) or wt than 25% -, strength dispersions (Surelease ®) performed in the market and as such are also preferably used as the coating material
  • the retardant coating in the medicament of the invention preferably carnauba wax, beeswax, glycerol monostearate, glycerol monobehenate (Compritol ATO888 ® ), Glycerinditripalmitostearat (Precirol ATO5 ® ), microcrystalline wax, cetyl alcohol, cetylstearyl alcohol or Have mixture of at least two of these components.
  • the coating dispersion or solution may, in addition to the corresponding polymer, have a customary physiologically compatible plasticizer known to the person skilled in the art in order to lower the necessary minimum film temperature.
  • Suitable plasticizers are, for example, lipophilic diesters of an aliphatic or aromatic dicarboxylic acid with C 6 -C 40 and an aliphatic alcohol with C 1 -C 8 , such as dibutyl phthalate, diethyl phthalate, dibutyl sebacate or diethyl sebacate, hydrophilic or lipophilic esters of citric acid, such as triethyl citrate, tributyl citrate, acetyl tributyl citrate or acetyl triethyl citrate, polyalkylene glycols such as polyethylene glycols or propylene glycols, esters of glycerol, such as triacetin, Myvacet ® (acetylated mono- and diglycerides, C 23 H 44 O 5 to C 25 H 47 O 7), medium-chain triglycerides (Miglyol ® ), oleic acid or mixtures of at least two of the above Welch
  • the retardant coating contains the plasticizer (s) in amounts of from 5 to 50% by weight, particularly preferably from 10 to 40% by weight and very particularly preferably from 10 to 30% by weight, based on the amount of polymer used.
  • plasticizers preferably up to 110% by weight, based on the amount of cellulose acetate.
  • the retardant coating may comprise further customary auxiliaries known to the person skilled in the art, such as, for example, lubricants, preferably talc or glycerol monostearate, color pigments, preferably iron oxides or titanium dioxide, or surfactants, for example Tween 80® .
  • auxiliaries known to the person skilled in the art, such as, for example, lubricants, preferably talc or glycerol monostearate, color pigments, preferably iron oxides or titanium dioxide, or surfactants, for example Tween 80® .
  • the release profile of the sustained-release active ingredient can be adjusted by the usual methods known to the person skilled in the art, for example by the thickness of the coating or by the use of further auxiliaries as constituents of the coating.
  • auxiliaries are, for example, hydrophilic or pH-dependent pore formers, for example sodium carboxymethylcellulose, cellulose acetate phthalate, hydroxypropylmethylcellulose acetate succinate, lactose, polyethylene glycol or mannitol or water-soluble polymers, for example polyvinylpyrrolidone or water-soluble celluloses, preferably hydroxypropylmethylcellulose or hydroxypropylcellulose.
  • the sustained-release coating can also contain insoluble or lipophilic excipients, such as, alkylated silica, which for example is managed as Aerosil ® R972 on the market, or magnesium stearate for further reinforcing the retardation.
  • insoluble or lipophilic excipients such as, alkylated silica, which for example is managed as Aerosil ® R972 on the market, or magnesium stearate for further reinforcing the retardation.
  • the respective formulation of the medicament according to the invention may optionally have, in addition to the retarding coating, at least one further coating.
  • This may, for example, be a flavor enhancement coating or an enteric coating.
  • the enteric coating is preferably based on methacrylic acid / methyl methacrylate copolymers with a molar ratio of the respective monomers of 1: 1 (Eudragit L ®), methacrylic acid / methyl methacrylate copolymers with a molar ratio of the respective monomers of 1: 2 (Eudragit S ®), methacrylic acid / ethyl acrylate copolymers with a molar ratio of the respective monomers of 1: 1 (Eudragit L30D-55 ®), methacrylic acid / methyl acrylate / methyl methacrylate copolymers with a molar ratio of respective monomers 7: 3: 1 (Eudragit FS ®), shellac Hydroxypropylmethylcellulosescetatsuccinat.
  • Cellulose acetate phthalate or a mixture of at least two of these abovementioned components which if appropriate also in combination with the abovementioned water-insoluble poly (meth) acrylates, preferably may be used in combination with Eudragit NE30D ® and / or Eudragit RL ® and / or Eudragit RS ®.
  • the coatings may be prepared by conventional methods suitable for the particular coating, methods known to those skilled in the art, e.g. by spraying solutions, dispersions or suspensions, by melting or by powder application methods.
  • the solutions, dispersions or suspensions may be used in the form of aqueous and / or organic solutions or dispersions.
  • aqueous dispersions are preferably used.
  • organic solvents alcohols, for example, ethanol or isopropanol, ketones, e.g. Acetone, esters, for example ethyl acetate, chlorinated hydrocarbons, e.g. Dichloromethane can be used, with alcohols or ketones are particularly preferably used. It is also possible to use mixtures of at least two of the abovementioned solvents.
  • the retarding topcoat is preferably applied so that the multiparticulate forms containing the active substance salt after their preparation with the corresponding polymers and optionally another active ingredient and / or the same Active salt and optionally other physiologically acceptable excipients from aqueous and / or organic media, preferably from aqueous media, coated by means of the fluidized bed process and preferably dry the coating simultaneously at ordinary temperatures in the fluidized bed and optionally annealed if necessary.
  • the coating is dried for poly (meth) acrylate coatings at a supply air temperature in the range of 30 to 50 ° C, more preferably in the range of 35 to 45 ° C.
  • the drying is preferably carried out at a temperature in the range of 50 to 80 ° C, more preferably in the range of 55 to 65 ° C.
  • Wax coatings can be applied by melt coating in the fluidized bed and cooled at temperatures below the respective melting range after coating for complete solidification.
  • the application of wax coatings can also be done by spraying their solutions in organic solvents.
  • the pharmaceutical according to the invention may also contain the pharmaceutical salt to be retarded in a retarding matrix, preferably evenly distributed.
  • hydrophilic materials which are known to the person skilled in the art.
  • the hydrophilic matrix materials are polymers, more preferably cellulose ethers. Cellulose esters and / or acrylic resins used. Very particular preference is given as matrix materials to ethylcellulose. Hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxymethyl cellulose. Poly (meth) acrylic acid and / or its derivatives, e.g. their salts, amides or esters used.
  • hydrophobic materials such as hydrophobic polymers, waxes, fats, long-chain fatty acids, fatty alcohols or corresponding esters or ethers, or mixtures of at least two of the aforementioned materials.
  • Mono- or diglycerides of C 12 -C 30 fatty acids and / or C 12 -C 30 fatty alcohols and / or waxes or mixtures of at least two of the abovementioned materials are particularly preferably used as hydrophobic materials.
  • the preparation of the retarding matrix can be carried out by the customary methods known to the person skilled in the art.
  • Another object of the invention is also the use of at least one pharmaceutical salt according to the invention and optionally physiologically acceptable excipients for the preparation of a medicament.
  • the corresponding drugs can be used for the treatment of the indications known for the respective active ingredients.
  • the salts preferably being the saccharinates.
  • At least one pharmaceutical salt according to the invention for the preparation of a medicament for the treatment of urinary incontinence, the salts used being preferably the saccharinates.
  • the amount of the respective pharmaceutical salt to be administered to the patient varies, for example, depending on the weight of the patient, the indication and the severity of the pain or the disease.
  • the person skilled in the art is aware of the dosages which are to be administered in order to achieve the desired effect on account of the properties of the particular active ingredients.
  • the pharmaceutical salts of a pharmaceutical active ingredient and a sugar substitute according to the invention are usually distinguished from the conventionally used salts of these active ingredients by a lower solubility in water.
  • these are the saccharinates of the respective active ingredients
  • the water solubility is usually ⁇ 250 mg / ml of water and compared to the water solubility of the conventional salts of the corresponding active ingredient is usually reduced by at least 50%.
  • the pharmaceutical salts according to the invention furthermore enable a more effective retardation of the active compound with conventional slow-release methods as compared to commonly used salts due to the changed solubility.
  • sustained-release drugs containing these pharmaceutical salts of the present invention can be produced more easily and inexpensively. This also applies to other modifications of the medicaments of the invention such. B. with enteric coatings.
  • the medicaments according to the invention in orally administered form, which release the respective active substance already at or immediately after the application, furthermore have the advantage that their strongly bitter or disgusting taste is compensated by the simultaneous release of the sugar substitute. This improves compliance with the dosage regulation in patients and the Medicines containing the respective active ingredient as a salt are more widely accepted.
  • the medicaments according to the invention are also suitable for diabetics.
  • water solubility of an active substance salt is not known, it can be determined according to the method given below, after which the water solubility of the pharmaceutical salts according to the invention has also been determined:
  • (+) - (1S, 2S) -3- (3-dimethylamino-1-ethyl-2-methylpropyl) -phenol saccharinate 2.58 g (10 mmol) of (+) - (1S, 2S) -3 - (3-Dimethylamino-1-ethyl 2-methyl-propyl) -phenol hydrochloride and 2.42 g (10 mmol) of saccharin sodium dihydrate in each case completely dissolved with heating in the smallest possible amount of water. Subsequently, both solutions were mixed with stirring and then placed cool overnight.
  • diphenhydramine saccharinate For the preparation of diphenhydramine saccharinate, 5.0 g (17.1 mmol) of diphenhydramine hydrochloride and 4.13 g (17.1 mmol) of saccharin sodium dihydrate were each completely dissolved with heating in the smallest possible amount of water. Subsequently, both solutions were stirred together mixed and then cooled overnight. The precipitated Diphenhydraminsaccharinat was separated from the supernatant mother liquor, cleaned with ethanol and isolated by conventional methods.
  • Verapamllsaccharinat 415 mg (0.845 mmol) of verapemil hydrochloride and 204 mg (0.845 mmol) of saccharin sodium dihydrate were each completely dissolved with heating in the smallest possible amount of water Then both solutions were mixed with stirring and then cooled overnight. The precipitated verapamil saccharinate was separated from the supernatant mother liquor, purified with ethanol and isolated by conventional methods.
  • morphine saccharinate To prepare morphine saccharinate, 285 mg (0.76 mmol) of morphine hydrochloride trihydrate and 183 mg (0.76 mmol) of saccharin sodium dihydrate were in each case completely dissolved with heating in the smallest possible amount of water. Subsequently, both solutions were mixed together with stirring and then cooled overnight. The precipitated morphine saccharinate was separated from the supernatant mother liquor, purified with ethanol and isolated by conventional methods.
  • the taste test revealed that the chewing gums containing the diphenhydramine saccharinate initially had excellent taste and were still edible even after prolonged chewing time.
  • the water solubility of certain pharmaceutical salts and of conventional salts of the corresponding active ingredient was determined by the method given above.
  • the solubility values thus obtained are shown in Table 1 below; ⁇ b> Table 1: ⁇ / b> Comparison of the water solubilities of certain pharmaceutical salts according to the invention and corresponding conventional salts of these active substances.
  • the conventional salt used in each case is indicated in Klammem.

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Abstract

La présente invention concerne des sels pharmaceutiques constitués d'un principe actif pharmaceutique et d'au moins un succédané du sucre, des médicaments contenant ces sels et l'utilisation de ces sels pour la production de médicaments.

Claims (16)

  1. Sel pharmaceutique d'une substance active pharmaceutique et d'au moins un produit de remplacement du sucre, caractérisé en ce que la substance active est un composé formant un sel, choisi dans le groupe formé par (1RS,2RS)-3-(3-diméthylamino-1-hydroxy-1,2-diméthylpropyl)phénol, (-)-(1R,2R)-3-(3-diméthylamino-1-éthyl-2-méthylpropyl)-phénol, (+)-(1S,2S)-3-(3-diméthylamino-1-éthyl-2-méthylpropyl)phénol, (2RS,3RS)-1-diméthylamino-3-(3-méthoxyphényl)-2-méthylpentan-3-ol, (-)-(1S,2S)-3-(3-diméthylamino-1-éthyl-1-fluoro-2-méthylpropyl)-phénol, (+)-(1R,2R)-3-(3-diméthylamino-1-hydroxy-1,2-diméthylpropyl)phénol, (+)-(2R,3R)-1-diméthylamino-3-(3-méthoxyphényl)-2-méthylpentan-3-ol et (-)-(2S,3S)-1-diméthylamino-3-(3-méthoxyphényl)-2-méthylpentan-3-ol.
  2. Sel pharmaceutique selon la revendication 1, caractérisé en ce que la solubilité du sel dans l'eau est ≤ 250 mg/ml d'eau, de préférence ≤ 200 mg/ml, de manière particulièrement préférée ≤ 150 mg/ml, de manière tout particulièrement préférée ≤ 100 mg/ml.
  3. Sel pharmaceutique selon la revendication 1 ou 2, caractérisé en ce que le produit de remplacement du sucre formant un sel est la saccharine, le cyclamate ou l'acésulfame, de préférence la saccharine.
  4. Médicament contenant au moins un sel pharmaceutique selon l'une quelconque des revendications 1 à 3 et le cas échéant des adjuvants physiologiquement acceptables.
  5. Médicament contenant au moins un sel pharmaceutique selon l'une quelconque des revendications 1 à 3 pour lutter contre les douleurs.
  6. Médicament contenant au moins un sel pharmaceutique selon l'une quelconque des revendications 1 à 3 pour le traitement de l'incontinence urinaire.
  7. Médicament selon l'une quelconque des revendications 4 à 6, caractérisé en ce qu'il est formulé sous forme de gels, de gommes à mâcher, de jus, de sprays, de comprimés, de comprimés à mâcher, de dragées, de poudres, le cas échéant transvasées dans des capsules, de préparations sèches facilement reconstituables, de préférence sous forme de gels, de jus aqueux ou huileux, de sprays sublinguaux, de comprimés ou de comprimés à mâcher.
  8. Médicament selon l'une quelconque des revendications 4 à 6, caractérisé en ce qu'il est formulé sous forme multiparticulaire, de préférence sous forme de microcomprimés, de microcapsules, de granulés, de cristaux de substances actives ou de pellets, de manière particulièrement préférée sous forme de microcomprimés, de granulés ou de pellets, le cas échéant transvasé dans des capsules ou pressé en comprimés.
  9. Médicament selon l'une quelconque des revendications 4 à 8, caractérisé en ce que le sel se trouve au moins partiellement sous une forme retardée.
  10. Médicament selon la revendication 9, caractérisé en ce que le retard est réalisé par l'application d'un revêtement à effet de retard, l'incorporation dans une matrice à effet de retard, la fixation sur une résine échangeuse d'ions ou par une combinaison d'au moins deux de ces procédés.
  11. Médicament selon la revendication 10, caractérisé en ce que le revêtement à effet de retard est à base d'un polymère naturel ou synthétique, insoluble dans l'eau, le cas échéant modifié, le cas échéant en combinaison avec un plastifiant usuel ou à base d'une cire ou d'une graisse ou d'un alcool gras naturel, semi-synthétique ou synthétique ou d'un mélange d'au moins deux de ces composants.
  12. Médicament selon la revendication 10, caractérisé en ce que la matrice est à base d'un matériau de type matrice hydrophile, de préférence de polymères hydrophiles, de manière particulièrement préférée à base d'éthers de cellulose, d'esters de cellulose et/ou de résines acryliques, de manière tout particulièrement préférée à base d'éthylcellulose, d'hydroxypropylméthylcellulose, d'hydroxypropylcellulose, d'hydroxyméthylcellulose, de poly(acide (méth)acrylique) et/ou de leurs sels, amides et/ou esters.
  13. Médicament selon la revendication 10, caractérisé en ce que la matrice est à base d'un matériau de type matrice hydrophobe, de préférence de polymères hydrophobes, de cires, de graisses, d'acides gras à longue chaîne, d'alcools gras ou d'esters ou d'éthers correspondants ou de leurs mélanges, de manière particulièrement préférée à base de monoglycérides ou de diglycérides d'acides gras en C12-C3o et/ou d' alcools gras en C12-C30 et/ou de cires ou de leurs mélanges.
  14. Médicament selon l'une quelconque des revendications 4 à 13, caractérisé en ce qu'il présente un revêtement de protection, de préférence un revêtement de protection résistant au suc gastrique.
  15. Utilisation d'au moins un sel pharmaceutique selon l'une quelconque des revendications 1 à 3 pour la préparation d'un médicament destiné à lutter contre les douleurs.
  16. Utilisation d'au moins un sel pharmaceutique selon l'une quelconque des revendications 1 à 3 pour la préparation d'un médicament destiné au traitement de l'incontinence urinaire.
EP02716816A 2001-02-28 2002-02-28 Sels pharmaceutiques des composés 1-phenyl-3-dimethylamino-propaniques Expired - Lifetime EP1390023B1 (fr)

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DE10109763A DE10109763A1 (de) 2001-02-28 2001-02-28 Pharmazeutische Salze
PCT/EP2002/002169 WO2002067916A2 (fr) 2001-02-28 2002-02-28 Sels pharmaceutiques

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WO2002067916A3 (fr) 2003-12-18
CN101125137A (zh) 2008-02-20
ZA200410015B (en) 2005-09-28
PE20020973A1 (es) 2002-10-26
ZA200306529B (en) 2005-03-30
JP2004527491A (ja) 2004-09-09
NZ528302A (en) 2007-02-23
NZ551440A (en) 2007-08-31
CA2439269C (fr) 2011-11-01
RU2003127396A (ru) 2005-03-20
PT1390023E (pt) 2008-07-30
CN1561203A (zh) 2005-01-05
ATE395053T1 (de) 2008-05-15
HUP0303325A3 (en) 2008-03-28
NO20033815L (no) 2003-09-09
JP2011079843A (ja) 2011-04-21
SI1390023T1 (sl) 2008-10-31
HU229048B1 (hu) 2013-07-29
WO2002067916A2 (fr) 2002-09-06
ES2307739T3 (es) 2008-12-01
WO2002067651A2 (fr) 2002-09-06
IL157477A (en) 2009-12-24
MXPA03007712A (es) 2004-03-16
PL364223A1 (en) 2004-12-13
IL157477A0 (en) 2004-03-28
CZ306998B6 (cs) 2017-11-08
DE10109763A1 (de) 2002-09-05
BR0207726A (pt) 2004-07-27
DE50212273D1 (de) 2008-06-26
HK1064035A1 (zh) 2005-01-21
HUP0303325A2 (hu) 2004-01-28
CA2725635A1 (fr) 2002-09-06
CA2439269A1 (fr) 2002-09-06
JP4737583B2 (ja) 2011-08-03
SK10612003A3 (sk) 2004-01-08
KR20030078943A (ko) 2003-10-08
SK287574B6 (sk) 2011-03-04
PL218187B1 (pl) 2014-10-31
CZ20032315A3 (cs) 2003-11-12
EP1390023A2 (fr) 2004-02-25
RU2309942C2 (ru) 2007-11-10
AR033423A1 (es) 2003-12-17
CN100352431C (zh) 2007-12-05
NO20033815D0 (no) 2003-08-27
NO333986B1 (no) 2013-11-04

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